(5-nitro-2-furyl)-pyridines

ABSTRACT

COMPOUNDS OF THE FORMULA   2-A,R,(5-(O2N-)-FUR-2-YL)-PYRIDINE   WHEREIN A IS HYDROXYL, CHLORINE, ALKOXY OF 1 TO 10 CARBON ATOMS, DIMETHYLAMINO-ETHOXY OR DIETHYLAMINO-ETHOXY, AND R IS HYDROGEN, ALKYL OR 1 TO 4 CARBON ATOMS, PYRIDYL, PHENYL OR CHLORO-, HYDROXY- AND/OR NITRO-SUBSTITUTED PHENYL; THE COMPOUNDS ARE USEFUL AS ANTIMICROBIAL AGENTS, ESPECIALLY AGAINST GRAMNEGATIVE MICROORGANISMS, FOR THE TREATMENT OF INFECTIONS OF THE INTESTINAL AND UROGENITAL TRACT.

United States Patent US. Cl. 260-297 Z 6 Claims ABSTRACT OF THE DISCLOSURE Compounds of the formula wherein A is hydroxyl, chlorine, alkoxy of 1 to 10 carbon atoms, dirnethylamino-ethoxy or diethylamino-ethoxy, and R is hydrogen, alkyl of 1 to 4 carbon atoms, pyridyl, phenyl or chloro-, hydroxyand/or nitro-substitnted phenyl;

the compounds are useful as antimicrobial agents, especially against gramnegative microorganisms, for the treatment of infections of the intestinal and urogenital tract.

This invention relates to novel (5-nitro-2-furyl)-pyridines, as well as to a method of preparing these compounds.

More particularly, the present invention relates to a novel class of nitrofuryl-substituted pyridines of the formula wherein A is hydroxyl, chlorine, alkoxy of 1 to carbon atoms, dimethylamino-ethoxy or diethylamino-ethoxy, and

R is hydrogen, alkyl of 1 to 4 carbon atoms, pyridyl, phenyl or chloro-, hydroxyand/or nitro-substituted phenyl,

and, when A is hydroxyl, the tautomeric pyridones thereof.

The compounds embraced by formula I may be prepared by nitrating a 2-furyl-pyridine of the formula wherein R and A have the same meanings as in formula I, pursuant to conventional methods, such as by reaction with a mixture of concentrated "nitric acid and concentrated sulfuric acid at a temperature between 20 and +20 C.

The starting compounds of the formula II, in turn, may be prepared by 55 following methods:

3,829,426 Patented Aug-.3 13, 1974 "ice Method A By first preparing an a,5-unsaturated ketone of the formula wherein R has the same meanings as in formula I, pur

suant or analogous to the procedure described in Arch. Pharm. 297 (1964), 42 et seq., and subjecting said ketone to a condensation reaction with a pyridinium salt of the formula wherein X is halogen, preferably chlorine, pursuant or analogous to the procedure described in Chem. Ber. (1957), 711, whereby a compound of the formula wherein R has the meanings defined in connection with formula I, is obtained.

Method B By reacting an c p-unsaturated ketone of the formula III with a pyridinium salt of the formula 0 r Y mo-iiz-cni if -x wherein R is methyl or ethyl and X is halogen, preferably chlorine, in the presence of ammonium acetate and of a suitable solvent medium, preferably glacial acetic acid or ethanol, pursuant or analogousto the procedure described in Chem. Ber. 103 (1970), 322, whereby a compound of the formula V is also formed.

Method C By reacting a Mannich base of the formula I bwrn-crn-z wherein Z is secondary amine, such as dimethylamino o'r piperidino, or a salt thereof, with a pyridinium salt of theformula VI under the conditions set forth in method B, whereby the compound of the formula OH 0 o (VIII) is obtained.

Method D By subjecting Z-acetyl-furan to a condensation reaction with a pyridyl-aldehyde (see German Offenlegungsschrift 2,001,819) in the presence of perchloric acid to form a ketone of the formula which may then be cyclized pursuant to method A or B with a pyridinium salt of the formula IV or VI to yield a compound of the formula Method B By subjecting Z-acetyl-furan to a condensation reaction with an aliphatic or aromatic aldehyde (with the exception of a pyridyl-aldehyde referred to in method D) to form an a,5-unsaturated ketone of the formula LE-0111mm,

wherein R has the meanings defined for R in formula I except hydrogen, 2-pyridyl, 3-pyridyl and 4-pyridyl, which may then be cyclized with a pyridinium salt of the formula IV or VI to yield a compound of the formula wherein R: has the meanings defined above.

Method F 'Ihe compounds of the formula H wherein A is hydroxyl exist in tautomeric equilibrium with the corresponding pyridones R s l i on 0 \N E wherein R has the same meanings as in formula I.

Method G For the preparation of a compound of the formula o R \N/ (XIV) wherein R has the same meanings as in formula I and R is alkyl of 1 to carbon atoms, dimethylamino-ethyl or diethylamino-ethyl, by reacting a compound of the formula XIII with an alkali metal alcoholate, preferably with a sodium alcoholate of the formula R ONa (XV) wherein R, has the meanings defined above, advantageously in a suitable solvent medium at elevated temperatures, preferably between and 200 C. Examples of suitable solvent media are, in addition to an excess of an alcohol of the formula R OH, where R has the meanings previously defined, also inert solvents, such as acetonitrile, toluene, dimethylformamide or dioxane.

The following examples further illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited solely to the particular examples given below.

EXAMPLE 1 4-(5 '-Nitro-2-furyl) -6 (2"-pyridyl) -2 1H) -pyridone (a) l-(Furyl-Z')-3(pyridyl-2" )-propen-( 1 )-one- (3 4 liters of 1N sodium hydroxide were cooled to 0 C. in a vessel having a capacity of 10 liters, and then, while stirring, a mixture consisting of 605 gm. (5 mols) of 2- acetyl-pyridine and 480 gm. (5 mols) of 2 -furaldehyde was allowed to flow into the vessel over a period of one hour. Thereafter, the reaction mixture was stirred for one hour more at 0 C., then vacuum-filtered, and the filter cake was washed with 10 liters of water, dried and recrystallized from benzene/cyclohexane, yielding 96.5% of theory of the ketone of the formula ElCHnHJ'E which had a melting point of 50-51 C.

(b) 2-(Pyridyl-2')-4-(furyl-2")-pyridone-(6) by Method A.A mixture consisting of 800 gm. (4 mols) of the ketone obtained in (a), 965 gm. (4.8 mols) of carbethoxymethyl-pyridinium chloride, 2.4 kg. of ammonium acetate and 2.5 liters of ethanol was refluxed for one hour. Thereafter the still hot reaction solution was collected by vacuum filtration and recrystallized from ethanol, yielding 89% of theory of the compound of the tautomeric formulas OH O which had a melting point of 207-208" C.

(0) 476.5 gm. (2 mols) of the end product obtained in (b) were introduced into 1.5 liters of concentrated sulfuric acid at 4050 C., while stirring. The resulting mixture was cooled to 0 C., and then a mixture consisting of ml. of concentrated nitric acid (d=l.53; 2.4 mols) and 200 ml. of concentrated sulfuric acid was added dropwise thereto over a period of two hours. The resulting dark solution was then poured into 8 liters of water, the precipitate formed thereby was collected by vacuum filtration and again suspended in about 8 liters of water, and the aqueous suspension was admixed with ammoniumhydroxide until it reacted distinctly alkaline. The alkaline aqueous mixture was again vacuum-filtered, and the filter cake was washed with an ample amount of water and recrystallized from glacial acetic acid, yielding 92% of theory of the tautomeric formulas l l O oml M N-H (a) 1-(Pyridyl-4) 3 (furyl 2")-propen-(1)-one- (3).A mixture consisting of 100 gm. (0.03 mol) of pyridine 4 aldehyde, 103 gm. (0.93 mol) of 2-acetylfuran, 100 ml. of 70% perchloric acid and 300 ml. of toluene was stirred at 70-80" C. for one hour. Thereafter, the crystalline precipitate was collected by vacuum filtration and washed with a little cold methanol, yielding 83 gm. of the perchlorate of the olefinic ketone of the formula ULCHH which had a melting point of 195 C.

(b) 2-(Furyl 2') 4 (pyridyl-4")-pyridone-6 by method D.-83 gm. (0.2 mol) of the product obtained in (a) and 38 gm. (0.2 mol) of (N-carbamoyl-methyD- pyridinium chloride were dissolved in 250 ml. of methanol, 24 gm. (0.4 mol) of sodium methylate were added to the solution, and the mixture was allowed to stand overnight at room temperature. Thereafter, the reaction mixture was acidified with glacial acetic acid, and the resulting solution was evaporated on a water bath. The solid residue was triturated with water and then vacuum-filtered, and the filter cake was washed with water and methanol, yielding 67 gm. of the compound of the tautomeric formulas which had a melting point of 225226 C.

(c) Using a procedure analogous to that described in in Example 1(c), the compound of the tautomeric formulas having a melting point of 3103l4 C. was obtained from the end product obtained in (b).

6 EXAMPLE 3 (a) (,s-Dimethylamino ethyl) (furyl 2) ketone hydrochloride-440 gm. (4 mols) of Z-acetyl-furan, 240 gm. (8 mols) of paraformaldehyde and 406 gm. (5 mols) of dimethylamine hydrochloride were suspended in 960 ml. of ethanol, 10 ml. of concentrated hydrochloric acid were added to the suspension, and the resulting mixture was boiled for four hours, accompanied by stirring. Thereafter, the reaction mixture was allowed to cool, and the crystalline precipitate was collected by vacuum filtration, yielding 73% of theory of the Mannich salt of the formula which had a melting point of 18018l C.

(b) 6-(Furyl-2') 2(1H) pyridone by method C.

0 43.5 gm. (0.55 mol) of pyridine were heated to 100 C.,

and then 61 gm. (0.5 mol) of ethyl chloroacetate were added dropwise at a rate such that the temperature of the mixture was held at C. without exterior heating. After all of the chloroacetate had been added and the reaction had subsided, the molten mixture was taken up in 300 ml. of ethanol, 0.5 mol of the Mannich salt obtained in (a) and 300 gm. of ammonium acetate were added to the solution, and the mixture was. refluxed for 2.5 hours. Thereafter, the ethanol was distilled off in vacuo, the residue was triturated with about 200 ml. of water, and the crystalline product was collected by vacuum filtration and recrystallized from isopropanol, yielding 56% of theory of the compound of the tautomeric formulas which had a melting point of l68-169 C.

(0) Using a procedure analogous to that described in Example 1(c), the compound of the tautomeric formulas having a melting point of 280 C. (decomp.) after recrystallization from dioxane was obtained from the end product obtained in (b).

EXAMPLE 4 2-(p'Dimethylamino-ethoxy)-6-(5'nitro-2'- furyl pyridine (a) Z-(fi Dimethylarnino-ethoxy) 6 (furyl 2')- pyridine by method G.A mixture consisting of 8.05 gm. (0.05 mol) of the end product of Example 3(b), 10.5 gm. of potassium carbonate and 80 ml. of dimethylformamide was heated to -130 C., and then, while stirring, a total of 8.6 gm. (0.06 mol) of Z-dimethylaminoethyl chloride hydrochloride were added in small portions over a period of about two hours. The resulting mixture was stirred for five hours more at 120-430 C. and was then poured into 300 ml. of water, and the aqueous phase was separated and extracted with ether. The ethereal extract was dried over potassium carbonate, evaporated, and the residue was distilled in vacuo, yielding the compound of the formula which had a b.p. of 107l08 C. at 0.05 mm. Hg.

(b) The end product obtained in (a) was nitrated in the manner described in Example 1(c), the nitration reaction mixture was poured into water, and the resulting clear solution was neutralized with ammonia. The resulting clear solution was neutralized with ammonia. The resulting aqueous solution was extracted with ether, the ethereal extract was dried and evaporated, and the residue was taken up in gasoline and caused to crystallize therefrom by deep cooling. The compound of the formula O NlQJ-Q-O-CEI -CH -hKCHs):

with a melting point of 42-44 C. was obtained.

EXAMPLE 2- (Pyridyl-Z -4- (5"-nitro-2"-furyl) -6-chloro-pyridine (a) 2-(Pyridy1-2') 4 (furyl-Z")-6-chloro-pyridine by method F.A mixture consisting of 23.8 gm. (0.1 mol) of the end product of Example 1(1)) and 50 ml. of phosphorus oxychloride was heated for 5 hours at 150 C. in a closed tube. Thereafter, the reaction mixture was introduced into ice water, and the aqueous mixture was neutralized with sodium hydroxide. The crystalline precipitate formed thereby was collected by vacuum filtration and recrystallized from isopropanol, yielding the compound of the formula which had a melting point of 168-170 C.

(b) Using a procedure analogous to that described in Example 1(c), the compound of the formula having a melting point of 174-175 C. was obtained from the end product obtained in (a).

EXAMPLE 6 2- (Pyridyl-Z')-4-(5"-nitro-2"-furyl)-6-methoxypyridine (a) 2-'(Pyridyl-2')-4-(fury1-2")-6-methoxy-pyridine by method G.A mixture consisting of 10 gm. (0.04 mol) of the end product of Example 5(a), 5.5 gm. (0.1 mol) of sodium methylate and 100 ml. of methanol was heated for 5 hours at 150 C. in a pressure vessel. Thereafter, the reaction solution was evaporated, the residue was taken up in water, the aqueous mixture was vacuum-filtered, and the filter cake was recrystallized from cyclohexane, yielding the compound of the formula l! Re? which had a melting point of 124 C.

(b) Using a procedure analogous to that described in Example 1(c), the compound of the formula -I OCH; i k3 8 having a melting point of 209-210" C. was obtained from the end product of (a).

EXAMPLE 7 Using a procedure analogous to that described in Example l(c), 2-(5-nitro-2'-furyl)-4-(pyridyl-4")-6-chloropyridine, m.p. 249250 C., of the formula was obtained from Z-(furyl-Z')-4(pyridine-4")-6-chloropyridine.

EXAMPLE 8 Using a procedure analogous to that described in Example 1(c), 2-(5'-nitro-2-furyl)-6-methoxy pyridine, m.p. 136-l38 C., of the formula 0H o mul l /N s; oml N-H was obtained from 4-(furyl-2')-6-(pyridyl-4")-2(1H)- pyridone.

EXAMPLE 12 Using a procedure analogous to that described in Example 1(0), 2-(pyridyl-4)-4-(5-nitro-2"-furyl)-6-methoxy-pyridine, m.p. 158-160 C., of the formula was obtained from 2- (pyridyl-4 )-4- (furyl-Z") -6-methoxypyridine.

EXAMPLE 13 Using a procedure analogous to that described in Example 1(c), 2-(pyridyl-3')-4-(5"-nitro-2-furyl)-6-methoxy-pyridine, mp. 16817l C., was obtained from 2- (pyridyl-3 -4- (furyl-Z" -6-rnethoxy-pyridine.

EXAMPLE 14 Using a procedure analogous to that described in Example 1(c), 4-(5'-nitro-2'-furyl)-6-(pyridyl-3)-2(1H)- pyridone, mp. 320-322 C., of the tautomeric formulas CH: was obtained from 2-methy1-4-(furyl-2)-6-methoxy-pyridine.

EXAMPLE 16 Using a procedure analogous to that described in Example 1(c), 4-(5'nitro-2-furyl)-6-methyl 2(lH)-pyridone, m.p. 312-316 C., of the tautomerie formulas was obtained from 4-(fury1-2')-6-methyl-2(1H)-pyridone. EXAMPLE 17 Using a procedure analogous to that described in Example 1(c), 2 methyl-4(5-nitro-2-furyl)-6n-propoxypyridine, m.p. 95-100 C., was obtained from 2-methyl- 4 (furyl-Z' )-6-n-pro p oxy-pyridine.

EXAMPLE 18 Using a procedure analogous to that described in Example 1(c), 2 methyl-L(5'-nitro-2'-furyl)-6-(fl-diethy1- aminoethoxy) pyridine, m.p. 7879 C., of the formula W -CHr-CHz-N (C1115);

OzN o /N CH; was obtained from 2 methyl-4-(furyl-2)-6-(,B-diethylaminoethoxy)-pyridine.

EXAMPLE 19 Using a procedure analogous to that described in Example 1(c), 2 methyl-4(5'-nitr0-2'-fury1)6-n-decyloxypyridine, mp. 52-54 C., was obtained from 2-methyl-4- (furyl-Z)-6-n-decyloxy-pyridine.

EXAMPLE 20 Using a procedure analogous to that described in Example 1(c) 6-isopropyl-4-(5'-nitro-2'-furyl)-2(1H)-pyridone, m.p. 290-293 C., of the tautomeric formulas 10 was obtained from 6-isopropyl-4-(turyl-2')-2(lH)-pyridone.

EXAMPLE 21 Using a procedure analogous to that described in Example 1(c), 6-(5'-nitro-2-furyl)-4-(3", -dinitro-4-hydroxy-phenyl)-2-(1H)-pyridone, mp. 284-285" C., of the tautomeric formulas I v v I ON -NO; NO;

i OH L,

was obtained from 6 (furyl-Z')-4-(3,5"-dinitro-4-hydroxyphenyl)-2(1H)-pyrid0ne.

EXAMPLE 22 Using a procedure analogous to that described in Example 1(c), 6-(5'-nitro 2' furyl)-4 (p-chloro-.phenyl)- 2(1H)-pyridone, rn.p. 320 C.;.-of the tautomeric formulas i on \N oml Oml M o o 0 E was obtained from 6-(furyl-2') 4 (pchloro-phenyl-2 (1H)-pyridone.

EXAMPLE 23 Using a procedure analogous to that describedjn Example 1(c), 6 (5'-nitro-2-furyl)A(pyridyl-2")-2(1I}I) pyridone, m.p. 298-300 C., of the tautomeric formulas was obtained from 6-(furyl-2)-4-(pyridyl-2")-2 (1H) pyridone. v

EXAMPLE 24 Using a procedure analogous to that described in Ex ample 1(c), 2 chloro-4-(pyridyl-2)-6-(5"-nitro-2"furyl)-pyridine, m.p. 2142l6 C., was obtained from 2- chloro-4- (pyridyl-Z 6- (furyl-2" -pyridine.

EXAMPLE 25 Using a procedure analogousto that described in Example 1(c) 6 (5 nitro 2' furyl)-4-(pyridyl-3")- 2(1H)-pyridone, m.p. 300 C., was obtained from 6-(furyl-2 -4- pyridyl-3" -2 1H) -pyn'done.

EXAMPLE 26 Using a procedure analogous to that described in Example 1(c), 2-chloro-4-(pyridyl-3) 6 (5-nitro-2"- furyl)-pyridine, m.p. 228-229 C., was obtained from 2- chloro-4- pyridyl-3 -6- (furyl-2" -pyridine.

1 1 EXAMPLE 27 Using a procedure analogous to that described in Example 1(c), 2-meth0xy 4 (PyTidyl-3')-6-(5-nitro-2"- turyl)pyridine,. m.p. 187l88 C., was obtained from 2- methoxy-4-(pyridyl-3)-6-(furyl-2)-pyridine.

- EXAMPLE 28 Using a procedure analogous to that described in Example 1(c), 6-(5-nitro 2' furyl)-4-(p-nitro-phenyl)- 2(1H)-pyridone, m.p. 330-335 C., of the tautomeric formulas NO: NO:

nCsH1 n-CaH1 l l l l l OzN I OH OzN O O O I]! H was obtained from 6-(furyl-2')-4-n-propyl-2(lH)-pyridone.

The compounds embraced by formula I have useful pharmacodynamic properties. More particularly, they exhibit antimicrobial activity against a broad spectrum of pathogenic bacteria, fungi and protozoa, such as Staph. aureus, Streptoc.; E. coli, Salmonellen, Shigellen, Klebsilla pneum; Trich, menL; Trichomonas vag., Trichomonas foet.; Entamoeba hist., especially against gramnegative microorganisms, coupled with low toxicity, and may therefore be etiectively used externally as well as internally, particularly for combatting infections of the intestinal and urogenital tract in warm-blooded animals, such as dogs, cats, horses and cattle.

Especially well suited for external use are those compounds of the formula I wherein R is alkyl, particularly methyl; for internal use, those wherein R is pyridyl are especially well suited. Among the latter 4-(5-nitro-2'-furyl) 6 (pyridyl-2") 2(1H)-pyridone is particularly preferred.

For pharmaceutical purposes the compounds according to the present invention are administered to warmblooded animals topically, perorally or parenterally as active ingredients in customary pharmaceutical compositions, that is, compositions consisting essentially of an inert pharmaceutical carrier and efiective amount of the active ingredient, such as tablets, coated pills, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories, ointments, tinctures and the like. An etfective amount of the compounds according to the present invention for internal administration is from 1.0 to 100.0 mgm./kg. body weight; their effective concentration in compositions for external application is from 0.1 to 10.0% by weight based on the total weight.

The following examples illustrate a few pharmaceutical compositions comprising a compound of the present invention as an active ingredient and represent 12 the best modes contemplated of putting the invention into practical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 30 Tablets The tablet composition is compounded from the following ingredients:

Parts 4-(5-Nitro-2-furyl) 6 (pyridyl 2")-2(1H)- pyridine l00.0 Corn starch 125.0 Lactose 85.0 Colloidal silicic acid 5.0 Soluble starch 8.0 Magnesium stearate 2.0

Total 325.0

Preparation The pyridine compound, the lactose and 110 parts of the corn starch are intimately admixed with each other, the mixture is granulated through a screen with the aid of an aqueous solution of the soluble starch, the dried granulate is admixed with the remaining ingredients, and the resulting composition is compressed into 324 mgm.- tablets in a conventional tablet-making machine. Each tablet contains mgm. of the pyridine compound and is an oral dosage unit composition with effective antimicrobial action.

EXAMPLE 31 Coated pills The pill core composition is compounded from the following ingredients:

Parts 4-(5'-Nitr0-2-furyl) 6 (PyIidyl-2")2-(1H)- pyridone 100.0 lactose 50.0 Corn starch 60.0 Colloidal silicic acid 3.0 Soluble starch 5.0 Magnesium stearate 2.0

Total 220.0

Preparation EXAMPLE 32 Suspension The suspension is compounded from the following ingredients:

Parts 6-( 5 -Nitro-2'-furyl)-2( 1H)-pyridone 5.0 Saccharose 20.0 Sodium carboxymethyl cellulose 2.0 Glycerin 5.0 Flavoring Q.s. Preservative Q.s. Demineralized water Q.s. ad 100 Preparation The ground mixture of the pyridine compound, the sodium carboxymethyl cellulose and the glycerin is stirred 13 into the solution of the saccharose and the preservative in the demineralized water, the cellulose was allowed to swell, and then the flavoring is added and the composition is homogenized. The resulting aqueous suspension is an oral dosage unit composition with effective antimicrobial action.

EXAMPLE 33 Lozenges The lozenge composition is compounded from the following ingredients:

Parts 6-(5'-Nitro-2-furyl)-2(lH)-pyridone 5.0 Glucose monohydrate 38 .0 Saccharose, powdered 200.0 Stearic acid 15.0

Total 600.0

Preparation The pyridine compound, the glucose and the saccharose are admixed with each other, the mixture is granulated through a screen with a solution of the stearic acid in 60 gm. of ethanol, and the dried granulate is compressed into 600 mgm.-lozenges. Each lozenge contains mgm. of the pyridine compound and is an oral dosage unit composition with effective antimicrobial action.

EXAMPLE 34 Tincture The tincture composition is compounded from the following ingredients:

Preparation The perfume, the Cremophor and the pyridine compound are dissolved in the ethanol, and then the mix ture of glycerin and demineralized water is slowly stirred into the ethanolic solution. The resulting tincture is a topical composition with effective antimicrobial action.

EXAMPLE 35 Ointment The ointment composition is compounded from the following ingredients:

Preparation The Vaseline, the ceresin, the Cremophor and the wool grease are intimately admixed with each other, the mixture is heated to 70 C., and then a mixture of the finely divided pyridine compound with the paratfin oil is stirred in. Subsequently, a solution of the preservative in the demineralized water at 70 C. is added, the resulting mixture is homogenized, the perfume is added, and the finished composition is stirred until it has cooled. The resulting ointment is a topical composition with efiective antimicrobial action.

14 Example 36 Cream The cream is compounded from the following ingredients:

Parts 4 (5'-'Nitro-2-furyl) -6-methyl-2-(B-diethylaminoethoxy)-pyridine 2.0 Stearyl alcohol 10.0 Yellow Vaseline 15.0 Yellow wax 5.0 Glycerin monostearate 3.0 Spermaceti 5.0 Cremophor O 1.0 Glycerin 10.0 Preservative Q.s. Perfume Q.s. Demineralized water Q.s. ad 100.0

Preparation The finely divided pyridine compound, the yellow vaseline, the yellow w-ax, the stearyl alcohol, the glycerin monostearate, the spermacet-i and the Cremophor are intimately admixed with each other, and the mixture is heated to 70 C. A solution of the preservative in the mixture of the glycerin and water at 70 C. is then added, the composition is homogenized, the perfume is added, and the finished cream is stirred until it has cooled. The cream is a topical composition with effective antimicrobial action.

Example 37 Powder Preparation The ingredients are admixed, and the mixture is milled into a powder which is a topical composition with effective antimicrobial action.

Analogous results are obtained when any one of the .other pyridine derivatives embraced by formula I is substituted for the particular pyridine compound in Examples 30 through 37. Likewise, the amount of active ingredient in these illustrative examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to these particular embodiments, and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

What is claimed is:

1. A compound of the formula em i on o \N wherein R is hydrogen, pyridyl, alkyl of 1 to 4 carbon atoms, phenyl, .p-chloro-phenyl, p-(alkyl of 1 to 4 carbon .atoms)-pheny1, p-nitro-phenyl or 3,5-dinitro- 4-hydroxy-phenyl, and

R ishydrogen, pyridyl or alkyl of 1 to 4 carbon atoms, 15

or a 2( 1H)-pyridone 'tautomer thereof.

2. A compound of claim wherein R and R are alkyl of 1 to 4 carbon atoms.

3. A compound of claim 1 wherein R and R are methyl.

4. A compound of claim 1 wherein R and R are UNITED STATES PATENTS 3,518,256 6/1970 Minami et a1 2'60297 R ALAN L. rROTMA'N, Primary Examiner US. Cl. X.R.

Patent No.

Inventor(s) UNITED STATES PATENT OFFICE v CERTIFICATE OF CORRECTION Dated Aug 3 197 It is certified that error appears in the aboveidentified patent and that said Letters Patent are hereuy corrected as shown below:

Col. 1 line 2,

Col. line ML,

'Schroder" should read SchrBder after "was" inserts poured into 8 1iters of water, and the precipitate formed thereby was Col. 5 line 71,- that portion of the formula which reads should read that portion of the formula which reads mg UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION latent No. 3329, 42 Dated g 3, 97

Inventor) LUDWIG SCI-IRODER, KLAUS THOMAS, HANNS GOETH or appears in the above-identified patent It is certified that err corrected as shown below:

and that said Letters Patent are hereby 001. 1 1 line 21, that portion of the formula which reads should read Signed and sealed thia 7th day of January 1975.

(SEAL) Att eSt:

McCOY M. GIBSON JR. C. MARSHALL DANN Attesting Oft"1c -2r Commissioner of Patents 

